Amphetamine and related drugs have highly important pharmaceutical properties and are used in a variety of applications. These compounds act by increasing levels of norepinephrine, serotonin, and dopamine in the brain. Some of the medical indications are (a) CNS drugs commonly used to treat attention-deficit disorder (ADD) and attention-deficit hyperactivity disorder (ADHD) in adults and children and (b) to treat symptoms of traumatic brain injury and the daytime drowsiness symptoms of narcolepsy and chronic fatigue syndrome. Just to mention a few drugs that contain Amphetamine and derivatives, Vyvanse, Adderall, and Dexedrine belong to this family of drugs.
Due to the major importance of Amphetamine derivatives, numerous synthetic methods for their synthesis and their derivatisation have been developed (e.g. patent WO/2006/121552). A general problem which has to be overcome is the fact that Amphetamines include a stereodefined amine center which is potentially subject to racemisation. As a result, only methods which suppress racemisation can be applied. At the same time, these methods do need to fulfil the standard economic requirements of high yields, high selectivity and low process costs. Typically such reactions involve a coupling agent. Due to the production application area, coupling reagents also need to be non-toxic to avoid any risk.
For the synthesis and derivatisation of most Amphetamine derivatives, a variety of different coupling reagents has been tested but so far none has fulfilled all of the above requirements.